The critical role of inflammation in obesity and T2D is now well established. Under this Grant, we have focused on defining the roles of components of the NCoR/SMRT co-repressor complexes in inflammation, including TBL1/TBLR1 and GPS2, and the development of a new technology that has permitted us to examine interactions between distant genomic regions. We have identified a new mechanism by which GPS2 protects cells against a hyper-infiammatory state, and we have uncovered novel roles of ncRNAs in targeting co-regulatory complexes to discreet locations In the nucleus with speciflc transcriptional functions. In this Project, we will capitalize on these recent discoveries to advance three new Specific Aims. In Specific Aim 1, we will delineate the molecular mechanisms by which GPS2, an NCoR/SMRT-associated protein, suppresses hyper-inflammatory transcriptional responses in both macrophages and adipose tissue. These studies will test the hypothesis that GPS2 functions to regulate PPARy activity and infiammatory responses by acting both in the nucleus as a component of NCoR co-repressor complexes, and at the plasma membrane as an inhibitor of cell surface receptors that mediate responses to inducers and amplifiers of inflammation. In Specific Aim II, we will define the molecular and physiological roles of SMRT in macrophages and adipocytes. In concert with the unexpected findings by Projects 1 and 3 that deletion of the related co-repressor NCoR from either adipocytes or macrophages results in protection from obesity- induced insulin resistance, these studies may facilitate the identification of chemicals/ligands that selectively regulate insulin-sensitizing functions of nuclear receptors, such as PPARy. In Specific Aim 111, we will test the hypothesis that pro-infiammatory gene activation requires regulated interactions of promoter-associated transcriptional co-regulators with non-coding RNAs resident in specific sub-nuclear architectural structures. We will investigate whether directed movements between these sub-nuclear structures are required for regulated gene expression. These studies will therefore explore conceptually new cellular mechanisms for transcriptional control of gene expression that may be targets for therapeutic intervention. RELEVANCE (See instructions): The proposed studies will be of significance in advancing our understanding of central pathogenic mechanisms that drive the development of insulin resistance and contribue to the development of future therapeutic approaches to prevent and treat type 2 diabetes.